to filling patterns - Heart · Brecker,Lee,Gibson although striking changes in filling velocities...

Br Heart J 1992;68:567-73

Relation of left ventricular isovolumic relaxationtime and incoordination to transmitral Dopplerfilling patterns

Stephen J D Brecker, Chiang H Lee, Derek G Gibson

AbstractObjective-To investigate factors dur-

ing isovolumic relaxation that determineDoppler filling patterns in patients withleft ventricular disease, and thus toidentify the underlying mechanisms.Design-85 patients (50 ischaemic

heart disease, 35 left ventricular hyper-trophy due to aortic stenosis) and 26controls were studied with Doppler andM mode echocardiography andphonocardiography. 16 patients under-went two studies on separate occasions,to find whether changes in isovolumicrelaxation time were reflected by achange in the Doppler A/E ratio.Setting-A tertiary cardiac referralcentre.Subjects-Patients referred for assess-

ment of coronary artery disease or aorticstenosis with left ventricular hyper-trophy.Main outcomes measures-Doppler

filling velocities during early (E wave)and late (A wave) diastole and the A/Eratio, acceleration of the E wave, digit-ised M mode indices of incoordinaterelaxation (change in cavity dimensionbefore mitral valve opening and timefrom minimum dimension to mitralvalve opening), isovolumic relaxationtime, M mode measures of diastolicfunction after mitral valve opening(peak rate of posterior wall thinning andpeak rate of dimension increase), andleft ventricular end diastolic pressure.Results-AIE correlated with age in

normal subjects (r = 0 74), to a lesserextent in left ventricular hypertrophy(r = 0-41), but not significantly inischaemic heart disease. In all patients,isovolumic relaxation time was signi-ficantly and negatively correlated withthe acceleration of the E wave, showingits fundamental relation to the force re-sponsible for early diastolic filling(r = - 0-71 for left ventricular hyper-trophy, and -074 for ischaemic heartdisease, p value < 0 01). In leftventricular hypertrophy and thoseischaemic patients without left ven-tricular dilatation A/E was correlatedboth with isovolumic relaxation time(r = 0-68 and 0-60 respectively), andwith incoordinate relaxation (r = 065and 0-61). In those ischaemic patientswith left ventricular dilatation, theinfluence of incoordination was lost and

isovolumic relaxation time became thedominant influence upon A/E(r = 082). Weak correlations of enddiastolic pressure and RR interval withA/E, became insignificant onceisovolumic relaxation time had beentaken into account. Isovolumic relaxa-tion time and incoordination togetheraccounted for over 50% of the variancein the A/E ratio in our patients.Isovolumic relaxation time and the A/Eratio were linearly related. Patients witha short isovolumic relaxation time hadevidence of considerable diastolic abnor-malities, despite a normal Doppler A/Eratio. In the 16 patients who had twoechocardiographic studies, changes inthe duration of isovolumic relaxationwere accompanied by a change in theDoppler A/E ratio. The relation betweenthese two variables, derived from thegroup as a whole was similar.Conclusions-The main factors

influencing the A/E ratio in patients withleft ventricular disease are two distinctproperties of isovolumic relaxation-namely the duration and the extent ofincoordinate wall motion. Filling pres-sure and RR interval are not significantindependent determinants, but act onlythrough an effect upon isovolumic relaxa-tion time. Age is an important influencein normal people, but this effect is atten-uated in left ventricular hypertrophyand lost in ischaemic ventricular disease.

(Br Heart J 1992;68:567-73)

The pattern ofdiastolic inflow into the ventriclecan be conveniently studied with pulsedDoppler echocardiography, and the ratio ofpeak atrial to early diastolic velocities (A/Eratio) has been used by many as an index ofunderlying left ventricular diastolic disease.' 2Yet the precise mechanisms responsible forfilling are complex and incompletely under-stood. In normal individuals, age is well recog-nised to be the primary determinant of the A/Eratio,3-5 although in disease states it is likely thatthis effect will be attenuated by other overridingfactors. As blood flow velocity is a function oftransmitral pressure gradient, relations withleft atrial or left ventricular end diastolic pres-sure have been sought and not surprisinglyhave been found. In different studies, however,the correlation ofthe early filling velocity and E/A with filling pressure, has been reported to bepositive,6` negative,9 and non-existent,'°

Cardiac Department,Royal BromptonNational Heart andLung Hospital, SydneyStreet, LondonS J D BreckerC H LeeD G GibsonCorrespondence toDr Derek G Gibson, CardiacDepartment, RoyalBrompton National Heartand Lung Hospital, SydneyStreet, London SW3 6NP.Accepted for publication22 June 1992

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Brecker, Lee, Gibson

although striking changes in filling velocitiesdue to acute alteration of loading conditionshave been documented both in animals,"' andpatients.213 Disturbances of the A/E ratio andpeak rapid filling velocity have been ascribed toabnormal relaxation,14-16 as well as to reducedatrial and ventricular compliance,2 17 18 whereasM mode studies have shown that in left ven-tricular hypertrophy, the A/E ratio may benormal in the presence of obvious diastolicdisease.'9 Our study is based on previous find-ings that the duration of isovolumic relaxationor the rate of left ventricular pressure declinemay affect early diastolic filling velocity inpatients with left ventricular hypertrophy'920or ischaemic heart disease.2' It was our aim toassess the extent to which filling velocitiesdepended on events occurring before mitralvalve opening, to identify the factors duringisovolumic relaxation that might be respon-sible, and thus to gain insight into underlyingmechanisms.

Patients and MethodsSTUDY POPULATIONWe studied 50 patients (42 men, eight women,mean age (range) 59 (37-81) years) withischaemic heart disease, 35 patients with leftventricular hypertrophy secondary to aorticstenosis (20 men, 15 women, mean age 56 (14-82) years), and a control group of 26 healthyindividuals (18 men, eight women, mean age 49(20-82) years). All patients had been referredfor echocardiographic evaluation of ventricularfunction. Cardiac catheterisation andmeasurement of end diastolic pressure werecarried out in 52 patients as part oftheir routineassessment.

M MODE AND CROSS SECTIONALECHOCARDIOGRAPHYM mode and cross sectional echocardiogramswith an Advanced Technical LaboratoryImager Mk 300I with a 3-0 MHz mechanicaltransducer, or a Toshiba SSH 160A imagerwith a 3-5 MHz transducer were taken with thepatient in the standard left lateral position.Phonocardiograms were recorded with aLeatham microphone with a low frequencyfilter. M mode echocardiograms were recordedwith simultaneous eletrocardiogram andphonocardiogram, on a Honeywell (Ecoline 22)strip chart recorder at a paper speed of 10 cm/s.Only records showing clear continuous echoesfrom the septum and posterior wall and clearmitral cusp separation were used. Aortic valveclosure (A2) was taken as the start of the firsthigh frequency vibration of the aortic compon-ent of the second heart sound recorded on thephonocardiogram, and was checked for validitywith the aortic echogram and the aortic closureartefact on the Doppler recordings. Leftventricular internal cavity dimensions weremeasured at end systole (A2) and end diastole(start of the QRS complex on the electrocar-diogram) with leading edge method, from theparasternal long axis view. Isovolumic relaxa-tion time was measured from A2 to the initialseparation of the mitral cusps on the M modeechogram. All measurements were made on

three cardiac cycles and the mean taken. Mmode echocardiograms were digitised with aTerminal Display Systems TDS 20 digitisingtablet as previously described.22 Measures ofincoordinate relaxation were taken as theincrease in transverse cavity dimension duringisovolumic relaxation expressed as a percentageof the total dimension change during the car-diac cycle, and the time interval from minimumcavity dimension to mitral valve opening. Thepeak rate of dimension increase (dD/dt), andthe peak rate ofposterior wall thinning (dW/dt)were also derived from the digitised traces.Once again, all measurements were made onthree cardiac cycles, and the mean taken.

DOPPLER ECHOCARDIOGRAPHYWe recorded Doppler signals with a DoptekSpectrascan and a 2-0 MHz transducer, and aToshiba SSH 160A with a 3-5 MHz trans-ducer. Peak transmitral flow velocities wereidentified by continuous wave from the apex,and were recorded in pulsed mode with a 3 mmgate, and 250 MHz wall filter. The peakvelocities of early E wave and atrial A wavetransmitral flow were recorded and the A/Eratio was calculated. The time from onset ofearly transmitral flow to the peak velocity wastaken as acceleration time, and the peakvelocity divided by acceleration time as earlydiastolic acceleration. The time interval ofaortic closure to the onset of transmitral flowwas also recorded. Records were taken withsimultaneous electrocardiogram and phono-cardiogram at a paper speed of 10 cm/s. Allmeasurements were made on three cardiaccycles and the mean taken.

CARDIAC CATHETERISATION52 patients from the two study groups under-went cardiac catheterisation as part of theirroutine assessment, from either the brachial orfemoral approach. Pressure was recordedbefore left ventricular angiography with a fluidfilled 7 or 8 French pigtail catheter attached to amanifold micromanometer transducer (MedexMedical), with zero taken at mid-chest level.The left ventricular end diastolic pressure wasmeasured at the point on the pressurewaveform corresponding to the onset of theQRS complex on the electrocardiogram. Themean of 10 cardiac cycles was recorded. Allstudies were performed within 48 hours of theechocardiographic examination.

STATISTICAL ANALYSISAll values are given as mean (SD). Differencesbetween mean values were compared byStudent's t test. Simple and stepwise regres-sion, multiple regression, and linear correlationwere performed to assess relation betweenvariables.

ResultsGROUP CHARACTERISTICSTable 1 summarises the description and com-parison of the subjects. The patients withischaemic heart disease were older than thenormal subjects, but no other significant dif-

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Relation of left ventricular isovolumic relaxation time and incoordination to transmitral Dopplerfilling patterns

Table I Characteristics of the groups (mean (SD))

Ischaemic heart Left ventricular Controlsdisease (n = 47) hypertrophy (n = 35) (n = 26)

Age (y) 59 (9)t 56 (19) 49 (17)LVEDD (cm) 5 9 ( 1)*t 4-8 (1-0) 5-0 (0 6)RR interval (ms) 800 (200)t 835 (140)t 930 (155)A wave velocity (m/s) 0-43 (0 29)*t 0-68 (0-3)t 0-54 (0-12)E wave velocity (m/s) 0 71 (0 20)* 0-86 (0 31)t 0-69 (0-17)E wave acceleration (M/S2) 11 7 (6-0) 9-3 (4-6) 11 4 (3-1)A/E ratio 0-72 (0 60) 0-87 (0 49) 0 79 (0 28)Isovolumic relaxation time 60 (35) 60 (25) 60 (10)(measured to mitral valve opening)(ms)

Aortic closure to start of 105 (40) 85 (30) 85 (10)transmitral flow (ms)

Change in dimension before mitral 23 (16)*t 16 (9)t 5 (4)valve opening

Minimum dimension to mitral valve 75 (45)t 70 (45)t 35 (20)opening (ms)

Peak rate of dimension increase 9-8 (3-8)t 9 7 (3 5)t 15 5 (4 8)(cm/s)

Peak rate of posterior wall 5-9 (2 9)t 6-7 (3 3)t 9-8 (2 5)thinning (cm/s)

LVEDP(mm Hg) 22(11) 21(8)

LVEDD, left ventricular end diastolic dimension; LVEDP, left ventricular end diastolicpressure; *p < 0-05 v group with left ventricular hypertrophy; tp < 0 05 v controls.

ferences existed with respect to age. Left ven-tricular end diastolic dimension was greater inpatients with ischaemic heart disease (5 9(1 1) cm) than both those with left ventricularhypertrophy (4-8 (1 0)) and the controls (5 0(0 6)). TheRR interval was significantly shorterin both patient groups compared with controls(800 (200) ms and 835 (140) v 930 (155)). Thesedifferences did not affect within group analysis.The mean value for peak E wave velocity was

greater in patients with left ventricular hyper-trophy than in both other groups (0-86 (0-31) v071 (0 20) and 0-69 (0-17) m/s), in whom themean value did not differ significantly. Themean value for peak A wave velocity was alsogreater in patients with left ventricular hyper-trophy than in the controls (0-68 (0 3) v 0-54(0- 12) m/s) so that the A/E ratio did not differsignificantly (0-87 (0 49) v 0 79 (0 28)), alth-ough the SD was clearly higher, reflecting thewide range of values for the A/E ratio seen inleft ventricular hypertrophy. Although the Awave velocity was less in patients withischaemic heart disease than normal (0-43(0 29) m/s), once again the mean A/E ratio didnotdiffersignificantlyfromnormal(0*72(0*60)),the high SD similarly reflects the wide range ofvalues seen in ischaemic heart disease. Themean value for E wave acceleration in the groupwith left ventricular hypertrophy was not sig-nificantly lower than the other two groups.

Table 2 Subgroup analysis of the group with ischaemic disease (mean (SD))

Dilated cavity Non-dilated cavity(LVEDD > 6 cm) (LVEDD < 6 cm)

Age (y) 56 (9)* 62 (9)tLVEDD (cm) 6-8 (0 5) 5 0 (0 8)Shortening fraction (%) 14-6 (4 5)* 231 (7-1)RR Interval (ms) 765 (200)t 840 (195)A wave velocity (m/s) 0-39 (0-31)t 0 47 (0 29)E wave velocity (m/s) 0 74 (0-17) 0-66 (0 22)A/E ratio 0 57 (0-52) 0 86 (0 65)Isovolumic relaxation time (ms) 55 (30) 70 (35)Change in dimension before mitral valve opening (%) 21 (14)t 25 (18)tMinimum dimension to mitral valve opening (ms) 70 (40)t 80 (45)tPeak rate of dimension increase (cm/s) 9 2 (3-1)t 10-4 (4-3)fPeak rate of posterior wall thinning (cm/s) 5 5 (2 8)t 6 2 (3)tLVEDP (mm Hg) 22 (9) 20 (12)

LVEDD, left ventricular end diastolic dimension; LVEDP, left ventricular end diastolicprcssure; *p < 0-05 v group with normal cavity dimension; tp < 0 05 v normal control group.

The mean values of isovolumic relaxationtime seen in each group were identical (60 (35),60 (25), 60 (10) ms), although the range ofvalues seen in both patient groups was muchwider than in the controls. The time fromaortic closure to the start offlow was significan-tly longer than the isovolumic relaxation timemeasured as aortic closure to the point ofmitralcusp separation in all groups. This discrepancywas 25 ms in left ventricular hypertrophy andnormal people, and 45 ms in those withischaemic heart disease. This discrepancy didnot significantly differ between those ischaemicpatients with and without incoordinate relaxa-tion. In both ischaemia and hypertrophy,measures of incoordination during isovolumicrelaxation were greater than in the controls,both as the percentage change in dimensionbefore mitral valve opening, and the timeinterval from minimum cavity dimensions tomitral valve opening. These two measureswere, as expected, highly correlated.Peak rates of dimension increase and pos-

terior wall thinning were significantly reducedin both patient groups compared with controls.

WITHIN GROUP COMPARISONCavity sizeTo investigate the effect of cavity dilatation, wedivided patients with ischaemic heart diseaseinto two groups according to the end diastolicdimension. Those with left ventricular dilata-tion were younger and with a significantlyreduced shortening fraction, but there were noother significant differences between the twogroups in terms of Doppler orM mode indicesof diastolic function. Indices of diastolic func-tion in both subgroups were significantly dif-ferent from normal (table 2).

Isovolumic relaxationFigure 1 shows that the isovolumic relaxationtime and the Doppler A/E ratio for all patientswith left ventricular disease were linearlyrelated. When subdivided into two groupsdepending on isovolumic relaxation time, thosewith shorter values had significantly lessincoordination and a greater peak rate ofdimension increase. Importantly however, bothsubgroups had M mode indices of diastolicfunction that were significantly different fromnormal (table 3).

+ Dilated ischaemic heart diseaseo Left ventricular hypertrophy. Nnn-.riBitatr inn.h2amir hp-art riisqwa-

0 0 00 0 *

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000 + oDC + +

0 20 40 60 80 100 120 140Isovolumic relaxation time (ms)

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Figure 1 Relation between Doppler A/E ratio andisovolumic relaxation timefor all three patient groups.The three regression lines were so similar that they arerepresented by a single line.

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Table 3 Subgroup analysis of all patients with left ventricular disease, based uponisovolumic relaxation time (mean (SD))

Variable IVRT < 60ms IVRT > 60ms

Isovolumic relaxation time (ms) 40 (15) 90 (20)Change in dimension before mitral valve opening (%) 15 (1 1)*t 27 (15)*Minimum dimension to mitral valve opening (ms) 55 (35)*t 90 (40)*Peak rate of dimension increase (cm/s) 10 8 (3 6)*t 8-7 (3 5)*Peak rate of posterior wall thinning (cm/s) 6 8 (3 3)* 5 7 (2.8)*LVEDP (mm Hg) 23 (9) 19 (9)

IVRT, isovolumic relaxation time; LVEDP, left ventricular end diastolic pressure; *p < 0 05 vnormal control subjects; tp < 0 05 v group with IVRT > 60 ms.

Effect of age on filling patternA/E correlated with age in normal individuals(r = 0 74), to a lesser extent in those withleft ventricular hypertrophy (r = 0-41), butnot significantly in those with ischaemic heartdisease (table 4).

SEPARATE EFFECTS OF ISOVOLUMIC RELAXATIONTIME AND INCOORDINATION UPON FILLINGPATTERNIn left ventricular hypertrophy and thoseischaemic patients without left ventriculardilatation, A/E was correlated both withisovolumic relaxation time (r = 0-68 and0 60 respectively), and with incoordinate relax-ation (measured as a percentage change beforemitral valve opening, r = 0 65 and 0-61,table 4). In those ischaemic patients with leftventricular dilatation (end diastolic dimension>6 cm), the influence of incoordination waslost and isovolumic relaxation time became thedominant influence upon A/E (r = 0-82).This was despite considerable incoordinaterelaxation being evident in this subgroup.Stepwise regression confirmed that weakcorrelations of end diastolic pressure and RRinterval with A/E became insignificant onceisovolumic relaxation time had been taken intoaccount. Multiple regression analysis for thegroup with ischaemic heart disease, and thatwith left ventricular hypertrophy, showed thatisovolumic relaxation time (IVRT) and incoor-dinate relaxation account for over 50% of thevariance in the Doppler A/E ratio.

In patients with ischaemic heart diseases, theregression equation was:A/E = -0-128 + 0 011 IVRT + 0 009%

change before mitral valve opening;R2 = 52%

In left ventricular hypertrophy, it was:A/E = -0095 + 0011 IVRT + 0017%

change before mitral valve opening;R= 60%

Table 4 Correlation coefficients of the AIE ratio

Left Ischaemic Ischaemicventricular heart disease heart disease

Controls hypertrophy non-dilated dilated

Age 0-74** 0 41* 0-28 0-23Isovolumic relaxation time 0-04 0-68** 0 60** 0 82**Incoordinate relaxation:Change in dimension before mitral 025 0 65** 0 61** 0-27

valve opening (%)Minimum dimension to mitral 0-15 0 72** 0 50** 0 22

valveopening (ms)

RR Interval 002 0 17 0 09 0-54**LVEDP -0 37* - 0-48* -0 2

LVEDP, left ventricular end diastolic pressure; *p < 0 05; **p < 0 01.

40 60 80 100 120Isovolumic relaxation time (ms)

Figure 2 Results of changes in the Doppler AIE ratioand isovolumic relaxation time in the seven patientsstudied on two occasions, with the largest changes. Thearrows indicate the direction of change and the broad linerepresents the regression line derivedfrom the group as awholefrom fig 1. Note that changes within individualpatients behave in a similar fashion to differences betweenpatients.

EFFECT OF ISOVOLUMIC RELAXATION TIME UPONACCELERATIONIsovolumic relaxation time correlated sig-nificantly with acceleration of early diastolicflow in both ischaemic heart disease(r = -0 74, p < 0-01), and left ven-tricular hypertrophy (r = -071,p < 001).

CHANGES WITHIN PATIENTSSixteen patients were studied more than once,and in all cases, changes in the duration ofisovolumic relaxation time were matched by aconcomitant change in the Doppler A/E ratio.The time between the two studies was 6 (5)months. Figure 2 shows the findings in theseven patients with the greatest changes. Somepatients had increased isovolumic relaxationtime and Doppler A/E ratio, and conversely,those whose isovolumic relaxation time gotshorter had a reduced A/E ratio. Figure 3shows the relation between the magnitude ofchange in isovolumic relaxation time and themagnitude of change in the A/E ratio for allpatients. These striking changes occurredwithout any evidence that the underlying dia-stolic properties of the left ventricle hadchanged (table 5).

0 100-

xX 80-a)

E g60-L-o a)

C.f 40-

ue 2Ca)D 20-

OF

0 0

0

* S

*0Ut

II0 0:5 1:0 15Change in Doppler A/E ratio

2-0

Figure 3 Relation between the size of change in theDoppler A/E ratio, plotted against the size of change inisovolumic relaxation time, in the 16 patients studied ontwo occasions.

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Table 5 Doppler A/E ratio, isovolumic relaxation time, and indices of diastolicfunction in 16 patients studied on two occasions: data are presentedfor the lower AIEratio and higher AIE ratio studies (mean (SD))

Value when AIE ratio Value when AIE ratiowas low was high

A/E ratio 0-46 (0-53) 1 01 (0-53)Isovolumic relaxation time (ms) 40 (35)* 80 (40)Peak rate of dimension increase (cm/s) 10-6 (3 4) 9 7 (4 1)Peak rate of posterior wall thinning (cm/s) 8.8 (2-3) 7-6 (3 6)

ip < 0 05 v group with higher A/E ratio.

DiscussionThe pattern of blood flow across the mitralvalve during diastole is not determined bythe presence or absence of left ventriculardisease, but by simple newtonian mechanics.Acceleration or deceleration ofblood is directlyproportional to the applied force. A force ismeasured in fluid as a pressure gradient-thatis, the rate of change of pressure with distancealong the direction offlow. A complete descrip-tion ofthe pressure gradients requires mappingof the three dimensional pressure field-thespatial distribution of pressure throughout theatrium, atrioventricular junction, and ventriclethroughout the filling period. Such measure-ments are so complex that they have never beenundertaken experimentally, let alone in intactpatients with heart disease. Single deter-minants of left atrial or left ventricularpressure, particularly with respect tophysiologically irrelevant reference points suchas atmospheric or mid right atrial pressure,have given rise to confusing reports thatattempt to relate filling pressures to Dopplermeasurements.6 910 In the present study,therefore, we have explored other interrela-tions with Doppler measurements of the trans-mitral flow pattern, and shown the importanceof two separate components of isovolumicrelaxation in determining filling patterns.There are an increasing number of publica-

tions relating isovolumic relaxation with earlyfilling velocity, peak filling rate, or the A/E ratioin hypertrophic cardiomyopathy,20 coronaryartery disease,2' left ventricular hypertrophy,'9and dilated cardiomyopathy.23 In the study ondilated cardiomyopathy, as in this study, A2 tomitral cusp separation Was used to measureisovolumic relaxation time. The discrepancybetween this and the time interval of A2 to thestart of flow on Doppler has been shown to be25 ms, on average, in controls and in leftventricular hypertrophy, and 50 ms in dilatedcardiomyopathy.24 We have now shown that inischaemic heart disease as a whole, thisdiscrepancy is 45 ms. Furthermore, we wereunable to show any significant differences in thisdiscrepancy between those ischaemic patientswith and without incoordination, suggestingthat the primary effect of the disturbance is todelay mitral valve opening itself, rather thanthe start of transmitral flow once the valve hasopened. In the present study we were able toshow an effect not simply on peak early diastolicflow velocity but on the peak initial accelerationof blood during early diastole. Further, theinfluence of isovolumic relaxation could be

resolved by stepwise regression analysis, intotwo discrete components: isovolumic relaxa-tion time itself and the extent of incoordinationduring isovolumic relaxation. Both wereindependently significant in patients with leftventricular hypertrophy or ischaemic heartdisease with normal cavity size. We havealready shown the importance of incoordina-tion in affecting rapid filling during early dia-stole,25 and the results of our patients withischaemic heart disease and normal cavity sizeare entirely compatible with this study. Inthose ischaemic patients with cavity dilatation,however, isovolumic relaxation time was theonly influence upon the A/E ratio. This was notdue to a lack of incoordination in the patientswith dilated ventricles; on the contrary, theyhad particularly incoordinate ventricles. Thisassociation between isovolumic relaxation andfilling was very significant in all three patientgroups with values of R2 (and thus theproportion of overall variance of filling patternaccounted for) consistently above 50%. Thisimplies that events before rather than aftermitral opening, were the dominant determin-ants ofboth the initial acceleration ofblood intothe left ventricle, and of the A/E ratio of thesepatients with ventricular disease.By definition a force is that which causes

acceleration. In being so closely associated withinitial acceleration, therefore, events duringisovolumic relaxation must also be closelyrelated to the forces causing blood flow from theleft atrium to the ventricle-that is, to theatrioventricular pressure gradient. Severalpotential mechanisms exist to explain thisconnection. Isovolumic relaxation time itselfhas already been shown to be closely related toleft ventricular filling pressure,26 which maypartly explain our findings. This simplerelation, however, would not account for theadditional effect of incoordination duringisovolumic relaxation. Incoordinate wallmotion is due to asynchronous termination ofsystole in different regions of the ventricle.27Clearly, this cannot be assessed in detail fromthe ventricular pressure pulse, but its overalleffect is likely to slow the rate of fall ofpressure,and thus to prolong isovolumic relaxation timeindependently of the pressure differencebetween the aorta and left atrium. Also, theearly diastolic pressure drop across the mitralvalve depends on the effective pressure withinthe left ventricle as well as the left atrium.Normally, left ventricular pressure in earlydiastole is negative to atmospheric pressure,reflecting the effectofrestoring forces within themyocardium at end systole.2"' Dissipation ofthese forces by incoordinate relaxation wouldthus increase effective ventricular pressuretowards zero by the time the mitral valve opensand so reduce the atrioventricular pressuregradient independently of any change inorthodox estimates of left atrial pressure (madewith respect to the atmosphere or mid rightatrium). The absence ofthe effect ofincoordina-tion on early diastolic acceleration in patientswith cavity dilatation, unlike its clear effect inthe other two groups, can also be explained onthis basis. We have already presented evidence

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suggesting that normal ventricular restoringforces are maintained in patients with leftventricular hypertrophy,3' but not in those withcavity dilatation and low ejection fraction.23 Ifrestoring forces are not generated at endsystole, then incoordinate wall motion duringisovolumic relaxation would not be expected toha-ve any further effect on early diastolic trans-mitral flow. These effects of incoordination arenot easy to reproduce in any experimentalmodel, and must thus be studied clinically.The linear relation between the Doppler A/E

ratio and isovolumic relaxation time has prac-tical consequences. If isovolumic relaxationtime is less than 60 ms, the A/E ratio will benormal (


19 Lee CH, Hogan JC, Gibson DG. Diastolic disease in leftventricular hypertrophy: comparison of M mode andDoppler echocardiography for the assessment of rapidventricular filling. Br Heart J 1991;65:194-200.

20 Sanderson JE, Gibson DG, Brown DJ, Goodwin JF. Leftventricular filling in hypertrophic cardiomyopathy. Anangiographic study. Br Heart J 1977;39:661-70.

21 Fioretti P, Brower RW, Meester GT, Serruys PW. Interac-tion of left ventricular relaxation and filling during earlydiastole in human subjects. Am J Cardiol 1980;46:197-203.

22 Gibson DG, Brown D. Measurement of instantaneous leftventricular dimension and filling rate in man, usingechocardiography. Br Heart J 1973;35:1141-9.

23 Ng KSK, Gibson DG. Relation of filling pattern to diastolicfunction in severe left ventricular disease. Br Heart J1990;63:209-14.

24 Lee CH, Vancheri F, Josen MS, Gibson DG. Discrepanciesin the measurement of isovolumic relaxation time: a studycomparing M mode and Doppler echocardiography. BrHeart J 1990;64:214-8.

25 Hui WKK, Gibson DG. Mechanisms of reduced leftventricular filling rate in coronary artery disease. Br HeartJ 1983;50:362-71.

26 Mattheos M, Shapiro E, Oldershaw PJ, Sacchetti R, GibsonDG. Non-invasive assessment of changes in leftventricular relaxation by combined phono-, echo-, andmechanocardiography. Br Heart J 1982;47:253-60.

27 Gibson DG, Prewitt TA, Brown DJ. Analysis of leftventricular wall movement during isovolumic relaxationand its relation to coronary artery disease. Br Heart J1976;38: 1010-9.

28 Suga H, Goto Y, Igarashi Y, Yamada 0, Nozawa T,Yasumura Y. Ventricular suction under zero sourcepressure for filling. Am J Physiol 1986;251:47-55.

29 Yellin EL, Hori M, Yoran C, Sonnenblick EH, Gabbay S,

Frater RWM. Left ventricular relaxation in the filling andnonfilling intact canine heart. Am J Physiol 1986;250:620-9.

30 Nikolic S, Yellin EL, Tamura K, et al. Passive properties ofcanine left ventricle: diastolic stiffness and restoring forces.Circ Res 1988;62:1210-22.

31 Park CH, ChowWH, Gibson DG. Phase differences betweenleft ventricular wall motion and transmitral flow in man:evidence for involvement of ventricular restoring forces innormal rapid filling. Int J Cardiol 1989;24:347-54.

32 Castello R, Pearson AC, Kern MJ, Labovitz AJ, Lenzen P.Diastolic function in patients undergoing coronary angio-plasty: Influence of degree of revascularisation. J Am CollCardiol 1990;15:1564-9.

33 Yellin E, Nikolic S, Frater RWM. Left ventricular fillingdynamics and diastolic function. Prog Cardiovasc Dis1990;32:247-7 1.

34 Doran JH, Traill TA, Brown DJ, Gibson DG. Detection ofabnormal left ventricular wall movement during iso-volumic contraction and early relaxation. Comparison ofecho-and angiocardiography. Br Heart J 1978;40:367-71.

35 Gibson DG, Doran JH, Traill TA, Brown DJ. Abnormal leftventricular wall movement during early systole in patientswith angina pectoris. Br Heart J 1978;40:758-66.

36 Brecker SJ, Stojnic BB, Xiao HB, Mbaissouroum M,Gibson DG. Prolonged right ventricular systole impairsleft ventricular filling in pulmonary hypertension[Abstract]. J Am Coll Cardiol 1992;19 (suppl A):394.

37 Zelinsky R, Diebold B, Raffoul H, Cohen A. Modifications ofthe mitral flow due to the presence of a left bundle branchblock (LBBB) [Abstract]. J Am Coll Cardiol 1988;11(suppl A):174.

38 Xiao HB, Lee CH, Gibson DG. Effect of left bundle branchblock on diastolic function in dilated cardiomyopathy. BrHeart J 1991;66:443-7.

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